Abstracts From the NCCN 2023 Annual Conference
Authors: Qing Deng, Minjae Lee, Farjana Fattah, Shohei Koyama, David Gerber, Esra Akbay, Erik Blomain, Anish Somani, Ajay Subramanian, Shaghayegh Soudi, Eniola Oladipo, Christin New, Deborah Kenney, Neda Nemat-Gorgani, Susan Hiniker, Alexander Chin, Raffi Avedian, Robert Steffner, David Mohler, Matt Van De Rijn, Everett Moding, Caitlin Zebley, Charmaine Brown, Tian Mi, Yiping Fan, Shanta Alli, Shannon Boi, Giovanni Galletti, Enrico Lugli, Deanna Langfitt, Jean-Yves Metais, Timothy Lockey, Michael Meagher, Brandon Triplett, Aimee Talleur, Stephen Gottschalk, Ben Youngblood, William Jackson, Krithika Suresh, Daniel Spratt, Robert Dess, Neethi Dasu, Kirti Dasu, Jason John, Yaser Khalid, Brian Blair, Lucy Joo, ; Foster
Journal: Journal of the National Comprehensive Cancer Network (2023)

Background: KRAS is the most commonly mutated oncogene in Lung adenocarcinoma (LUAD).Co-occurring mutations in tumor suppressors and a master kinase LKB1/ STK11 or TP53 define the major subgroups of KRASmutant LUAD with distinct biology and therapeutic vulnerabilities.Inactivating mutations in LKB1 occur in 31% of KRAS mutant LUAD, resulting in approximately 10,000-15,000 deaths annually in the US.KRAS and LKB1 comutated (KL) lung tumors represent one of the most aggressive LUAD subtypes and are resistant to immune checkpoint blockade (ICB) therapies.Thus, there is a critical need to identify differential therapeutic targets in KL tumors.Anti-tumor immunity can be mediated in part by cytotoxic T cells and natural killer (NK) cells, which have potent cytotoxic functions.T and NK cells can recognize tumors through expression of stress molecules.KL tumors express activating ligands NK cell activating receptor, The Natural Killer Group 2D (NKG2D).We hypothesized that KL tumors may be directed toward immune cell killing by targeting these surface molecules.Methods: We characterized NKG2DL RNA expression in NSCLC mouse models and patient samples.To validate the protein production we performed ELISA in patient blood samples.Expression in the mouse tumors was confirmed by flow cytometry of tumor tissues.We developed a fusion protein of NKG2D and Igg (antibody) to therapeutically target NKG2DLs in tumors.We then performed therapeutic experiments with the antibody in the genetically engineered mouse KL lung tumor models.We performed analysis of the tumor microenvironment by flow cytometry after treatment.Results: NKG2DL expression is increased in NSCLC cancer tissue as compared to healthy tissues of both in mouse and human tumors.NKG2DL was also detected in the blood of lung cancer patients.We observed significant tumor control and delayed growth in a KL model with an antibody targeting NKG2DLs.Combinations with standard of care further increased therapeutic efficacy of NKG2DL targeting antibody.Conclusions: ICB resistant NSCLCs can be vulnerable to targeting NKG2DLs.We propose that correct scheduling of existing clinically used treatments and NKG2DL targeting antibody treatment can activate innate and adaptive immunity.This therapy can be alternative treatment option in tumors that express NKG2DLs and are resistant to current standard of care.